The IL-7R complex is a heterodimeric receptor made up of the IL-7R alpha chain (IL-7Rα) and the common gamma chain (γc) (Mazzucchelli et al., Nat Rev Immunol., 2007, 7:144-54). IL-7R is bound by interleukin-7 (IL-7), a cytokine essential to the development and homeostatic maintenance of T and B lymphocytes (Fry et al., J Immunol., 2005, 174:6571-6). Binding of IL-7 to IL-7R activates multiple pathways that regulate lymphocyte survival, glucose uptake, proliferation and differentiation.
IL-7R is expressed on both dendritic cells and monocytes and appears to act in multiple hematopoietic lineages (Reche P A, et al., J. Immunol., 2001, 167:336-43). In dendritic cells, IL-7R plays an immunomodulatory role, whereas lymphocytes require IL-7R signaling for survival, proliferation and differentiation. Both the Jak-Stat and PI3K-Akt pathways are activated by the binding of IL-7 to IL-7R (Jian et al., Cytokine Growth Factor Rev., 2005, 16:513-533). These pathways involve signaling crosstalk, shared interaction domains, feedback loops, integrated gene regulation, multimerization and ligand competition. Some targets of IL-7 signaling, including Bcl2 and Pyk2, contribute to cellular survival. Other targets, such as PI3 kinase, src family kinases (lck and fyn) and STAT5, contribute to cellular proliferation. The transcription factor STAT5 contributes to activation of multiple different downstream genes in B and T cells and may contribute to VDJ recombination through alteration of chromatin structure. The cell survival and cell proliferation signals induced by IL-7 combine to induce normal T cell development. Details of the complex IL-7 signaling network and its interaction with other signaling cascades in cells of the immune system have not yet been fully elucidated.
From the information available in the art, and prior to the present invention, it remained unclear whether the introduction of an antagonist IL-7R antibody into the blood circulation to selectively antagonize IL-7R would be effective to treat type 2 diabetes, type 1 diabetes, GVHD, lupus and rheumatoid arthritis, and, if so, what properties of an IL-7R antibody are needed for such in vivo effectiveness.